Molecular Pathways: Regulation and Targeting of Kinetochore–Microtubule Attachment in Cancer

Herman, Jacob; Toledo, Chad M.; Olson, James M.; DeLuca, Jennifer G.; Paddison, Patrick J.

doi:10.1158/1078-0432.ccr-13-0645

Cited by 24 publications

(22 citation statements)

References 66 publications

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“…In contrast, we observed that in ~60% of GSCs, Ras-transformed cells, and HeLa cells its GLEBs domain becomes essential for viability to promote kinetochore-microtubule attachment (17). Mechanistic experiments demonstrated that oncogenic Ras signaling triggers alterations in kinetochore regulation resulting in added GLEBs domain requirement and the primary reason we observe differentially sensitivity to BUB1B knockdown (17,24). …”

Section: Introductionmentioning

confidence: 78%

“…To this end, we analyzed the RNA-seq profiles of 18 GSCs as well as astrocyte and neural progenitor cells, classifying them by BUB1B R/S status. BUB1B R/S status was determined by sensitivity to LV-shBUB1B and/or measurement of inter-kinetochore distance at metaphase (17,24) (Supplementary Table S1 and Supplementary Fig. S1).…”

Section: Resultsmentioning

confidence: 99%

“…BUB1B-inhibition sensitive (BUB1B S ) cells invariably have shorter metaphase inter-kinetochore distances (IKDs), or shorter average distances between sister kinetochores during mitosis when stable end-on microtubule attachments have formed (17,24). This serves as an indirect measure of the pulling forces generated by dynamic microtubules bound to kinetochores, such that stronger attachments lead to longer IKDs and weaker attachments produce shorter IKDs (24).…”

Section: Introductionmentioning

confidence: 99%

“…This serves as an indirect measure of the pulling forces generated by dynamic microtubules bound to kinetochores, such that stronger attachments lead to longer IKDs and weaker attachments produce shorter IKDs (24). Although IKDs are reliable predictors of BUB1B R/S and in theory could be used to predict tumor sensitivity to BUB1B inhibition, in practice, taking IKD measurements is laborious and time consuming, requiring confocal microscopic z-sectioning of mitotic cells, and unlikely to be useful to "type" tumor samples.…”

Section: Introductionmentioning

confidence: 99%

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Sensitivity toBUB1BInhibition Defines an Alternative Classification of Glioblastoma

et al. 2017

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Glioblastoma multiforme (GBM) remains a mainly incurable disease in desperate need of more effective treatments. In this study, we develop evidence that the mitotic spindle checkpoint molecule BUB1B may offer a predictive marker for aggressiveness and effective drug response. A subset of GBM tumor isolates require BUB1B to suppress lethal kinetochore-microtubule attachment defects. Using gene expression data from GBM stem-like cells, astrocytes and neural progenitor cells that are sensitive or resistant to BUB1B inhibition, we created a computational framework to predict sensitivity to BUB1B inhibition. Applying this framework to tumor expression data from patients, we stratified tumors into BUB1B sensitive (BUB1BS) or BUB1B resistant (BUB1BR) subtypes. Through this effort, we found that BUB1BS patients have a significantly worse prognosis regardless of tumor development subtype (i.e., classical, mesenchymal, neural, proneural). Functional genomic profiling of BUB1BR versus BUB1BS isolates revealed a differential reliance of genes enriched in the BUB1BS classifier, including those involved in mitotic cell cycle, microtubule organization and chromosome segregation. By comparing drug sensitivity profiles, we predicted BUB1BS cells to be more sensitive to type I and II topoisomerase inhibitors, Raf inhibitors and other drugs, and experimentally validated some of these predictions. Taken together, the results show that our BUB1BR/S classification of GBM tumors can predict clinical course and sensitivity to drug treatment.

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Section: Introductionmentioning

confidence: 78%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Sensitivity toBUB1BInhibition Defines an Alternative Classification of Glioblastoma

et al. 2017

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“…Loss of SAC function has been attributed to CIN and aneuploidy in several cancers (Kops et al . 2005, Herman et al . 2015).…”

Section: Unexplored Arenas For Potential Development Of Novel Cancmentioning

confidence: 99%

Targeting mitotic pathways for endocrine-related cancer therapeutics

Agarwal

Varma

2017

Endocrine-Related Cancer

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A colossal amount of basic research over the past few decades has provided unprecedented insights into the highly complex process of cell division. There is an ever-expanding catalogue of proteins that orchestrate, participate and coordinate in the exquisite processes of spindle formation, chromosome dynamics and the formation and regulation of kinetochore microtubule attachments. Use of classical microtubule poisons has still been widely and often successfully used to combat a variety of cancers but their non-selective interference in other crucial physiologic processes necessitate the identification of novel druggable components specific to the cell cycle/division pathway. Considering cell cycle deregulation, unscheduled proliferation, genomic instability and chromosomal instability as a hallmark of tumor cells, there lies an enormous untapped terrain that needs to be unearthed before a drug can pave its way from bench to bedside. This review attempts to systematically summarize the advances made in this context so far with an emphasis on endocrine-related cancers and the avenues for future progress to target mitotic mechanisms in an effort to combat these dreadful cancers.

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Measuring Kinetochore–Microtubule Attachment Stability in Cultured Cells

DeLuca

Herman

DeLuca

2016

Methods in Molecular Biology

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Duplicated sister chromatids connect to the mitotic spindle through kinetochores, large proteinaceous structures built at sites of centromeric heterochromatin. Kinetochores are responsible for harnessing the forces generated by microtubule polymerization and depolymerization to power chromosome movements. The fidelity of chromosome segregation relies on proper kinetochore function, as precise regulation of the attachment between kinetochores and microtubules is essential to prevent mitotic errors, which are linked to the initiation and progression of cancer and the formation of birth defects (Godek et al., Nat Rev Mol Cell Biol 16(1):57-64, 2014; Ricke and van Deursen, Semin Cell Dev Biol 22(6):559-565, 2011; Holland and Cleveland, EMBO Rep 13(6):501-514, 2012). Here we describe assays to quantitatively measure kinetochore-microtubule attachment stability in cultured cells.

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Molecular Pathways: Regulation and Targeting of Kinetochore–Microtubule Attachment in Cancer

Cited by 24 publications

References 66 publications

Sensitivity toBUB1BInhibition Defines an Alternative Classification of Glioblastoma

Sensitivity toBUB1BInhibition Defines an Alternative Classification of Glioblastoma

Targeting mitotic pathways for endocrine-related cancer therapeutics

Measuring Kinetochore–Microtubule Attachment Stability in Cultured Cells

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